Direct Site of Alcohol Action Found in the Brain

August 25, 2009

Even casual drinkers quickly become aware of alcohol-related impairments in cognitive function, such as poor decision-making, dulled reflexes, slurring of speech and stumbling movement. But exactly how alcohol affects the brain—whether it works directly on neurons or in a more indirect fashion by changing the environment around brain cells—has been a mystery.

Now, however, researchers have discovered a site that alcohol directly affects: a special type of ion channel that decreases the activity of neurons.

“Most drugs are large and somewhat complicated molecules. Their size and build-up gives them a ‘lock and key’ specificity, so they fit precisely in a pocket found on one or two proteins,” Harris says. “But alcohol is a tiny, simple molecule—really just a little more complicated than water—and doesn’t enter into these complicated binding arrangements. So it’s really been a mystery how alcohol works in the brain, how many sites it may bind with and just how it works.”

In 1999, Harris and colleagues discovered that a special type of ion channel in the neuronal membrane, the G-protein-coupled inwardly rectifying potassium channel (GIRK), showed enhanced function when exposed to intoxicating levels of alcohol. Other ion channels along the membrane did not.

The finding, published in Nature Neuroscience (pdf), did not specify the specific mechanism of action on the GIRK channel but did establish it as a site of increased interest in the study of alcohol’s effects on the nervous system.

Dampening neuronal excitability

That paved the way for Paul Slesinger and his colleagues at the Salk Institute for Biological Studies to examine the functions of GIRK channels.

“We know that these channels open up during periods of chemical communications between neurons,” Slesinger says. “And when they open up, they tend to decrease activity of the neurons. It’s kind of like the equivalent of a short circuit.”

In the new research, which appeared June 28 in Nature Neuroscience, Slesinger and Prafulla Aryal, a graduate student from the University of California, San Diego, partnered with structural biologist Senyon Choe to generate a 3-D image of the GIRK channel. The team also demonstrated a direct site of action for alcohol on the channel.

“We created a crystal structure of a GIRK channel down to its smallest components and found a hydrophobic pocket that was a good candidate for where alcohol might act on the channel,” Aryal says. The group then tested that pocket and found that, when stimulated with alcohol, the channel opened.

“The alcohol fits right in and acts like a lubricant to promote the channel spending more time in an open configuration,” Slesinger says. While in this open configuration, the channel then dampens the activity of the neuron and other neurons surrounding it.

Step forward

Both Slesinger and Aryal caution that this finding is unlikely to be the only way in which alcohol works on the brain. The alcohol molecule’s simple structure suggests that the ion channel is not the only binding site.

But better understanding of how this first known direct site of action for alcohol works may provide potential therapeutic targets not only for alcoholism but also for epilepsy, the scientists say.

“We have two ideas that are not necessarily related,” Slesinger says. “First, by having this 3-D picture of where alcohol interacts with the GIRK channel, it raises the possibility of finding some inhibitor or agonist that impacts the ability of alcohol to bind to the pocket. That sort of [molecule] could be used to treat alcohol dependence.”

In addition, he and his colleagues are interested in learning more about how the GIRK channel works in other disorders. For instance, the gating mechanism of the channel might yield treatment possibilities for epilepsy.

“With epilepsy, neurons are in a highly excited state,” Aryal says. “But if we understand how this pocket opens the GIRK channel, we can find other molecules that can open GIRK, dampen that excitability and then treat epilepsy.”

Slesinger is optimistic about the role of GIRK channels but says there is a lot more to learn about how alcohol and other chemicals in the brain affect them.

“We need many more studies to get to the point where we can talk specifics about any type of antagonist,” he says. “But I think the significance of this study points us in an exciting new direction.”

Harris, who was not involved with the new study, agrees that the finding is a step forward. “We found the GIRK channel was very sensitive to alcohol and established it as important but had just about given up on ever finding the site of action,” he says. “I’m pleased to see that at least one of the sites for alcohol action on the GIRK channel has now been defined so nicely.”

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New X-ray crystallography shows a binding site for alcohol in an ion channel that plays a key role in several brain functions associated with drugs of abuse and seizures. The top image is a detailed view of the alcohol binding pocket with the ethanol molecule shown in yellow and red. The bottom image shows where the molecule is within the ion channel. (Images courtesy of Paul Slesinger, Salk Institute for Biological Studies)